5-Azacytidine, a cytidine analog, is capable of causing undermethylation of newly synthesized DNA, and of reactivating dormant genes in tissue culture cells and in baboons. This drug has been administered in a variety of regimens to 10 people with Beta thalassemia and sickle cell anemia; Gamma globin synthesis was selectively increased in bone marrow cells of each patient leading to an increased hemoglobin level in each thalassemic patient, and to a reduced number of irreversibly sickled and dense cells (cells containing increased amounts of Hb S polymer) in those with sickle cell anemia. DNA hypomethylation has been directly demonstrated near the human Epsilon and Gamma globin genes within two days after treatment initiation, and increased levels of Lamda mRNA are present in bone marrow RNA at the same time. The rapidity of this switch suggest that 5-Azacytidine is capable of directly reactivating the Gamma genes in late erythroid precursor. Since the effect on Lamda globin synthesis persists for one to two weeks after the drug is stopped, earlier erythroid progenitors must also be effected by the drug. We have studied methylation patterns near nine genes, and have found that methylation decreases near all after treatment. However, globin hypomethylation does not result in reexpression of a variety of repressed genes, since RNA species from none of these other genes increase in concentration after treatment. These results suggest that 5-Azacytidine is not capable of dramatically altering the genetic repertoire of highly differentiated bone marrow cells.